Suvorexant Acutely Decreases Tau Phosphorylation and A beta in the Human CNS

Objective: In Alzheimer's disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid-beta levels and amyloid plaques in mouse models overexpressing amyloid-beta, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid-beta, tau, and phospho-tau. Methods: Thirty-eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid-beta, tau, and phospho-tau via immuno-precipitation and liquid chromatography-mass spectrometry. Results: The ratio of phosphorylated-tau-threonine-181 to unphosphorylated-tau-threonine-181, a measure of phosphorylation at this tau phosphosite, decreased similar to 10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau-serine-202 and tau-threonine-217 were not decreased by suvorexant. Suvorexant decreased amyloid-beta similar to 10% to 20% compared to placebo starting 5 hours after drug administration. Interpretation: In this study, suvorexant acutely decreased tau phosphorylation and amyloid-beta concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treatment insomnia andmay have potential as a repurposed drug for the prevention of Alzheimer's disease, however, future studies with chronic treatment are needed.